Prodrugs of carbamate inhibitors of IMPDH

Abstract

The present invention relates to novel compounds, methods of preparing these compounds, and pharmaceutical compositions comprising these compounds. These compounds are carbamate prodrugs that convert to active inhibitors of the IMPDH enzyme in vivo. The compounds and pharmaceutical compositions of this invention are particularly well suited for activation and subsequent inhibition of the IMPDH enzyme activity. Consequently, these prodrugs may be advantageously used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds and compositions of this invention.

What is claimed is:  
     
       1. A compound of Formula (I):                    
       wherein: 
       A is either B or is selected from:  
       (C 1 -C 6 )-alkyl, or (C 2 -C 6 )-alkenyl or alkynyl; and  
       A optionally comprises up to 2 substituents, wherein:  
       the first of said substituents, if present, is selected from R 1  or B, and  
       the second of said substituents, if present, is R 1 ; wherein:  
       each R 1  is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl or alkynyl, or (CH 2 ) n —W 1 ; wherein n is 0, 1 or 2; R 1  is optionally substituted with R 5 ; and  
       W 1  is selected from halogen, CN, NO 2 , CF 3 , OCF 3 , OH, S(C 1 -C 4 )-alkyl, SO(C 1 -C 4 )-alkyl, SO 2 (C 1 -C 4 )-alkyl, NH 2 , NH(C 1 -C 4 )-alkyl, N((C 1 -C 4 )-alkyl) 2 , N((C 1 -C 4 )-alkyl)R 8 , COOH, C(O)NH2, C(O)NH(C 1 -C 4 )-alkyl, C(O)N((C 1 -C 4 )-alkyl) 2 , —C(O)O(C 1 -C 4 )-alkyl or O(C 1 -C 4 )-alkyl; and  
       R 8  is an amino protecting group;  
       B is selected from a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH 2  adjacent to any of said N, O, or S heteroatoms is optionally replaced with C(O); and each B optionally comprises up to 3 substituents, wherein:  
       the first of said substituents, if present, is selected from R 1 , R 2 , R 4  or R 5 ,  
       the second of said substituents, if present, is selected from R 1  or R 4 , and  
       the third of said substituents, if present, is R 1 ; wherein:  
       each R 2  is independently selected from (C 1 -C 4 )-alkyl, or (C 2 -C 4 )-alkenyl or alkynyl; and each R 2  optionally comprises up to 2 substituents, wherein:  
       the first of said substituents, if present, is selected from R 1 , R 4  and R 5 , and  
       the second of said substituents, if present, is R 1 ;  
       each R 4  is independently selected from OR 5 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OP(O)(OR 6 ) 2 , SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , NC(O)C(O)R 6 , NC(O)C(O)R 5 , NC(O)C(O)OR 6 , NC(O)C(O)N(R 6 ) 2 , C(O)N(R 6 ) 2 , C(O)N(OR 6 )R 6 , C(O)N(OR 6 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , N(R 6 ) 2 , NR 6 C(O)R 1 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 6 , NR 6 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , N(OR 6 )R 6 , N(OR 6 )R 5 , OP(O)(OR 6 )N(R 6 ) 2 , and OP(O)(OR 6 ) 2 ;  
       each R 5  is a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH 2  adjacent to said N, O or S maybe replaced with C(O); and each R 5  optionally comprises up to 3 substituents, each of which, if present, is selected from 1,2- methylenedioxy, 1,2-ethylenedioxy, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl or alkynyl, or (CH 2 ) n —W 1 ; wherein n is 0, 1 or 2;  
       and wherein any R 5  heterocyclic ring in R 5  is optionally benzofused;  
       each R 6  is independently selected from H, (C 1 -C 5 )-alkyl, or (C 2 -C 5 )-alkenyl or alkynyl, and each R 6  optionally comprises a substituent that is R 5 ; and wherein  
       any carbon atom in any A, R 2  or R 6  is optionally replaced by O, S, SO, SO 2 , NH, or N(C 1 -C 4 )-alkyl;  
       D is selected from N(R 9 )—C(O)—N(R 9 ), C(O)—N(R 9 ), N(R 9 )—C(O), NR 9 —C(O)—C(R 10 )=C(R 10 );  
       each R 9  is independently selected from hydrogen, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl or alkynyl, R 5 -substituted-(C 1 -C 4 )-alkyl, or R 5 -substituted—(C 2 -C 4 )-alkenyl or alkynyl; wherein  
       R 9  is optionally substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;  
       each R 10  is independently selected from R 9 , W 4 —[C 1 -C 4 -alkyl], W 4 —[C 2 -C 4 -alkenyl or alkynyl], R 5 -substituted-[W 4 —[C 1 -C 4 -alkyl]], R 5 -substituted-[W 4 —[C 2 -C 4 -alkenyl or alkynyl]], O—R 5 , N(R 9 )—R 5 , S—R 5 , S(O)—R 5 , S(O) 2 —R 5 , S—C(O)H, N(R 9 )—C(O)H, or O—C(O)H; wherein:  
       W 4  is O, O—C (O), S, S(O), S(O) 2 , S—C(O), N(R 9 ), or N(R 9 )—C(O); and wherein  
       each R 10  is optionally and independently substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;  
       Z is C 1 -C 10 -alkylene, C 2 -C 10 -alkenyl or alkynyl, C 1 -C 10  aryl-substituted alkylene, C 2 -C 10  aryl-substituted alkenyl or alkynyl; wherein  
       up to 3 carbons may be replaced with —O—, —S—, —S(O)—, —S(O) 2 —, —NR 14 ; wherein  
       up to 3 —CH2— groups may be replaced with —C(O)—; wherein  
       up to 5 hydrogen atoms in any of said alkyl, alkenyl, aryl, or alkynyl are optionally and independently replaced by R 13  or R 5 ;  
       R 13  is halo, —OR 14 , —N(R 14 ) 2 , —SR 14 , —S(O)R 14 , —S(O) 2 R 14 , —S(O) 2 OR 14 , —S(O) 2 N(R 14 ) 2 , —N(R 14 )S(O) 2 N(R 14 ) 2 , —OS(O) 2 N(R 14 ) 2 , —NR 14 C(O)R 14 , —NR 14 C(O)OR 14 , —N(R 14 )C(O)N(R 14 ) 2 , —N(R 14 )C(S)N(R 14 ) 2 , —N(R 14 )C(NR 14 )N(R 14 ) 2 , —C(O)R 14 , —C(O)OR 14 , —C(O)SR 14 , —C(O)N(R 14 ) 2 , —C(NR 14 )N(R 14 ) 2 , —C(S)OR 14 , —C(S)N(R 14 ) 2 , —N(R 14 )P(O)(OR 14 ) 2 , —OP(O)(OR 14 ) 2 ;  
       R 14  is H, C 1 -C 5 -alkyl, C 2 -C 5 -alkenyl or alkynyl, aryl, or C 1 -C 5  alkyl-aryl; wherein  
       up to 3 hydrogen atoms in R  4  are optionally and independently replaced with a substituent that is R 13 ; and wherein  
       any NR 14 , taken together with the nitrogen and a carbon adjacent to the nitrogen, optionally forms a 5-7 membered ring, wherein said ring optionally contains up to three additional heteroatoms selected from O, N, S, or S(O) 2 ;  
       Y is —NH(R 14 );  
       R X  is (C 1 -C 6 )-alkyl, wherein up to 4 hydrogen atoms in said alkyl are optionally and independently replaced by R 20 ;  
       R 20  is independently selected from halo, —OR 21 , —N(R 22 ) 2 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —CN, or;  
       R 21  is selected from hydrogen, —(C 1 -C 6 )-straight alkyl, —(C 1 -C 6 )-straight alkyl-R 5 , —C(O)—(C 1 -C 6 )-alkyl which is optionally substituted with R 4 , —C(O)—R 5 , or —(C 1 -C 6 )-straight alkyl-CN;  
       each R 22  is independently selected from hydrogen, —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-alkyl-R 5 , —(C 1 -C 6 )-straight alkyl-CN, —(C 1 -C 6 )-straight alkyl-OH, —(C 1 -C 6 )-straight alkyl-OR 21 , —C(O)—(C 1 -C 6 )-alkyl, —C(O)—R 5 , —S(O) 2 —(C 1 -C 6 )-alkyl, or —S(O) 2 —R 5 ; or two R 22  moieties, when bound to the same nitrogen atom, are taken together with said nitrogen atom to form a 3 to 7-membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1 to 3 additional heteroatoms independently selected from N, O, or S;  
       R Y  is selected from hydrogen, —CF 3 , —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-alkyl-R 5 , or —R 5 ; or wherein R X  and R Y  are optionally taken together with the carbon atom to which they are bound to form a monocyclic or a bicyclic, saturated or unsaturated or aromatic, ring system consisting of 5 to 6 members per ring, wherein each ring optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH 2  adjacent to said N, O or S maybe replaced with C(O); wherein 1 to 4 hydrogen atoms in said ring system are optionally replaced by —OC(O)CH 3 , —O—CH 2 —C(O)OH, —O—CH 2 —C(O)O—(C 1 -C 4 )-alkyl, —O—CH 2 —CN, or —O—CH 2 —CH═CH 2 .  
     
     
       2. The compound according to  claim 1  wherein R X  and R Y  are taken together to form a 3-tetrahydrofuranyl moiety that is optionally substituted with —OC(O)CH 3 , —O—CH 2 —C(O)OH, —O—CH 2 —C(O)O—(C 1 -C 4 )-alkyl, —O—CH 2 —CN, or —O—CH 2 —CH═CH 2 . 
     
     
       3. The compound according to  claim 2  wherein the tetrahydrofuranyl moiety is not substituted. 
     
     
       4. The compound according to  claim 1  wherein B is a substituted phenyl group. 
     
     
       5. The compound according to  claim 1  wherein D is N(R 9 )—C(O)—N(R 9 ). 
     
     
       6. The compound according to  claim 5  wherein R 9  is hydrogen. 
     
     
       7. The compound according to  claim 1  wherein A is a substituted phenyl group and said first substituent is R 5 . 
     
     
       8. The compound according to  claim 7  wherein R 5  is oxazolyl. 
     
     
       9. The compound according to  claim 7  wherein said second substituent is R 2 . 
     
     
       10. The compound according to  claim 9  wherein R 2  is methoxy. 
     
     
       11. The compound according to  claim 1  wherein Z is C 2 -C 6  straight or branched alkyl or alkenyl; wherein 1 to 2 —CH 2 — groups are optionally replaced with —C(O)—, —O—, —S—, —S(O)—, or —S(O) 2 —, and another 1 to 2 —CH 2 — groups are optionally replaced with —CR 14 ; and wherein 1 to 2 hydrogen atoms are optionally replaced with R 13 . 
     
     
       12. The compound according to  claim 11  wherein Z is C 2 -C 6  straight or geminally branched alkyl or alkenyl; wherein 1 to 2 —CH 2 — groups are optionally replaced with —C(O)—; and another 1 to 2 —CH 2 — groups are optionally replaced with —NR 14 ; and wherein 1 hydrogen atom is optionally replaced with C(O)OR 14 ; wherein R 14  is selected from H, C 1 -C 5  straight or branched alkyl, C 2 -C 5  straight or branched alkenyl or alkynyl, aryl, or aryl substituted-C 1 -C 5  alkyl. 
     
     
       13. A composition comprising: 
       a. a compound according to any one of claims  1 - 10  in an amount effective to inhibit IMPDH activity following activation of said compound,  
       b. a carrier or adjuvant.  
     
     
       14. The composition according to  claim 13 , wherein said composition is formulated for pharmaceutical administration to a mammal.